In the US, 5% of women over age 60, and 28% over 85 may have dementia. We propose to capitalize on a large epidemiologic dataset with 22 years of prospective data to study risk factors for early cognitive impairment. While advances have been made to delay Alzheimer's disease progression, little research is aimed at studying the earliest stages of cognitive decline in healthy women, which might be most susceptible to intervention. Prior investigations have been largely cross-sectional, and smaller than the proposed study; virtually no studies have explored interactions between environment and genetic factors. We propose to examine prospectively how estrogen use, antioxidant intake, and anti- inflammatory drugs influence cognitive decline in non-demented women; we will examine the duration and dose of these agents, and explore interactions with genetic factors. The investigation will e conducted within the Nurses' Health Study, a cohort begun in 1976 with 121,700 women. Extensive data have been accumulated via biennial, mailed via biennial, mailed questionnaires, including duration, dose and frequency of use for all these agents, and other details. In 1989, blood samples were collected from 33,000; for those without blood samples, check brushings will be requested to obtain DNA. We will conduct three repeated tests of cognitive function by telephone, at two-year intervals, to 20,000 women aged 70-80, using well established and validated instruments. The interview takes 20-25 minutes to complete and includes tests of verbal fluency, working and episodic memory, delayed recall, executive function, and a brief version of the Mini-Mental State Examination. Initial testing in 1,668 women has been highly successful; the participation rate was 89% and 9% of subjects had scores which indicated cognitive impairment. Test cores were similar to those in studies of other populations. In second interviews of a smaller group after two years, 90% follow-up was maintained and mean decline in cognition was observed. The Nurses' Health Study provides a highly cost-efficient setting to examine lifestyle and genetic influences which may be instrumental in preventing or delaying early decline in cognitive function.